Identification of transient receptor potential cation channel, subfamily V member 1 (TRPV1), also known as capsaicin receptor, in 1997 was a milestone achievement in the research on temperature sensation and pain signalling. Very soon after it became evident that TRPV1 is implicated in a wide array of physiological processes in different peripheral tissues, as well as in the central nervous system, and thereby could be involved in the pathophysiology of numerous diseases. Increasing evidence suggests that modulation of TRPV1 may also affect seizure susceptibility and epilepsy. This channel is localized in brain regions associated with seizures and epilepsy, and its overexpression was found both in animal models of seizures and in brain samples from epileptic patients. Moreover, modulation of TRPV1 on non-neuronal cells (microglia, astrocytes, and/or peripheral immune cells) may have an impact on the neuroinflammatory processes that play a role in epilepsy and epileptogenesis. In this paper, we provide a comprehensive and critical overview of currently available data on TRPV1 as a possible molecular target for epilepsy management, trying to identify research gaps and future directions. Overall, several converging lines of evidence implicate TRPV1 channel as a potentially attractive target in epilepsy research but more studies are needed to exploit the possible role of TRPV1 in seizures/epilepsy and to evaluate the value of TRPV1 ligands as candidates for new antiseizure drugs.

BACKGROUND: Pruritus due to allergic skin disease is one of the most common reasons for dermatological consultations in the veterinary clinic. Treatment is usually multimodal and requires continuous monitoring and reassessment. New therapies are needed to broaden the therapeutic arsenal.
OBJECTIVE: The aim of this study was to evaluate the efficacy of a novel transient receptor potential vanilloid 1 (TRPV1) channel antagonist for allergic pododermatitis in dogs.
METHODS: Twenty-four client-owned dogs with allergic pododermatitis.
METHODS: The study was an open, prospective, multi-centre clinical trial with client-owned dogs. All dogs were treated twice daily with a spray containing hydroxymethoxyiodobenzyl glycolamide pelargonate for 28 days. Clinical assessments included pruritus Visual Analog Scale (PVAS), pedal skin lesion score, evaluation of quality of life (QoL), presence of secondary infections and a four-point subjective efficacy assessment by the veterinarian and the dog owner.
RESULTS: There was more than 50% improvement in all scores by the conclusion of the study. Secondary infections were reduced (p < 0.001). Both the veterinarians and dog owners evaluated the efficacy of the product positively. The product was well-tolerated.
CONCLUSIONS: This study demonstrated the tolerability and efficacy of a TRPV1 antagonist on pruritic pododermatitis in 24 dogs.
背景: 瘙痒是兽医诊所皮肤科诊断的最常见原因之一。治疗通常是多模式的，需要持续监测和重新评估。需要新的疗法来扩大治疗范围。 假设/目的: 评估一种新型瞬时受体电位香草酸1(TRPV1)通道拮抗剂治疗犬足皮炎的疗效。 动物: 客户饲养的24只足皮炎患犬。 材料和方法: 这项研究是一项开放的、前瞻性的、以客户饲养的犬为中心的临床试验。所有的犬每天用含有羟基甲氧基碘苄基乙酰胺壬酸酯的喷雾治疗两次，持续28天。临床评估包括瘙痒视觉模拟量表(PVAS)、爪部皮肤损伤评分、生活质量评估(QoL)、继发感染的存在以及兽医和犬主人的四点主观疗效评估。 结果: 到研究结束时，所有分数都有超过50%的改善。继发感染显著减少。兽医和犬主人都积极评价了该产品的功效。该产品耐受性良好。 结论和临床相关性: 本研究证明了TRPV1拮抗剂对犬瘙痒性足皮炎的耐受性和有效性。.
BACKGROUND: Le prurit constitue l\'un des motifs les plus fréquents de consultation en dermatologie vétérinaire. Le traitement est généralement multimodal et nécessite un monitoring et un suivi clinique réguliers. De nouvelles thérapeutiques sont nécessaires afin d’élargir l\'arsenal thérapeutique. HYPOTHÈSE/OBJECTIFS: Évaluer l\'efficacité d\'un nouvel antagoniste du canal « transient receptor potential vanilloid-1 » (TRPV1) dans la gestion des pododermatites chez le chien.
UNASSIGNED: 24 chiens détenus par des propriétaires atteints de pododermatite. MATÉRIELS ET MÉTHODES: L\'étude est un essai clinique ouvert, prospectif et multicentrique avec des chiens détenus par des clients. Tous les chiens ont été traités deux fois par jour avec un spray contenant du pélargonate d\'hydroxyméthoxyiodobenzylglycolamide pendant 28 jours. Les évaluations cliniques reposent sur une échelle visuelle analogique du prurit (PVAS), le score lésionnel cutané podal, l\'évaluation de la qualité de vie (QoL), la présence d\'infections secondaires et une évaluation subjective de l\'efficacité par le vétérinaire et le propriétaire du chien reposant sur quatre points. RÉSULTATS: On observe plus de 50 % d\'amélioration de l’ensemble des scores à l’issue de l\'étude. Les infections secondaires sont significativement diminuées. Les vétérinaires et les propriétaires de chiens évaluent favorablement l\'efficacité du produit. Le produit est bien toléré.
UNASSIGNED: Cette étude démontre la tolérance et l\'efficacité d\'un antagoniste du TRPV1 dans la gestion des pododermatites prurigineuses chez le chien.
UNASSIGNED: Juckreiz ist einer der häufigsten Gründe für dermatologische Konsultationen in der tierärztlichen Praxis. Die Behandlung ist in der Regel multimodal und benötigt ein kontinuierliches Monitoring und wiederkehrende Befundung. Es werden neue Therapien benötigt, um das therapeutische Repertoire zu erweitern.
UNASSIGNED: Das Ziel dieser Studie war die Evaluierung eines neuen Antagonisten des Transienten Rezeptor-Potential-Kationenkanal Vanilloid 1 (TRPV1) bei der Behandlung der Pododermatitis des Hundes.
UNASSIGNED: 24 Hunde in Privatbesitz mit einer Pododermatitis.
UNASSIGNED: Es handelte sich hierbei um eine offene, prospektive, multi-zentrische klinische Studie mit Hunden in Privatbesitz. Alle Hunde wurden zweimal täglich für 28 Tage mit einem Spray behandelt, der Hydroxymethoxyodobenzylglycolamid Pelargonate enthielt. Die klinische Beurteilung erfolgte mittels Pruritus Visual Analog Scale (PVAS), anhand der Beurteilung der Veränderungen an den Pfoten, einer Evaluierung der Lebensqualität (QoL) und des Auftretens von Sekundärinfektionen und einem subjektiven Vier-Punkte Wirksamkeitstest durch die VeterinärmedizinerInnen und durch die TierbesitzerInnen.
UNASSIGNED: Am Ende der Studie bestand eine mehr als 50%ige Verbesserung aller Werte. Die Sekundärinfektionen waren signifikant reduziert. Sowohl die TierärztInnen als auch die HundebesitzerInnen sprachen sich für eine positive Wirksamkeit dieses Produkts aus. Das Produkt wurde gut toleriert.
UNASSIGNED: Diese Studie zeigt die Verträglichkeit und Wirksamkeit eines TRPV1 Antagonisten bei der juckenden Pododermatitis von Hunden.
背景: 掻痒は、動物病院の皮膚科を受診する最も一般的な理由の一つである。治療は通常、多剤併用療法であり、継続的なモニタリングと再評価が必要である。治療法の幅を広げるために新しい治療法が必要である。 仮説/目的: 本研究の目的は、犬の肢端皮膚炎に対する新規のtransient receptor potential vanilloid 1(TRPV1)チャネル拮抗薬の有効性を評価することであった。 供試動物: 肢端皮膚炎を有するオーナー所有犬 24 頭。 材料と方法: 本試験は、オーナー所有犬を対象としたオープン前向き多施設共同臨床試験である。すべての犬に、hydroxymethoxyiodobenzyl glycolamide pelargonate含有スプレーを1日2回、28日間投与した。臨床評価は、痒みのVisual Analog Scale(PVAS)、足の皮膚病変スコア、QoL評価、二次感染の有無、獣医師と飼い主による4段階の主観的効果判定を行った。 結果: 試験終了時には、すべてのスコアが50%以上改善された。二次感染も有意に減少した。獣医師、飼い主ともに本剤の有効性を肯定的に評価した。また、本製品の忍容性は良好であった。 結論と臨床的関連性: 本研究は、痒みの伴う犬の肢端皮膚炎に対するTRPV1拮抗薬の忍容性および有効性を実証するものであった。.
UNASSIGNED: Prurido é uma das causas mais comuns de consultas dermatológicas na clínica veterinária. O tratamento é geralmente multimodal e requer monitoramento contínuo e reavaliação. Novas terapias são necessárias para ampliar o arsenal terapêutico. HIPÓTESE/OBJETIVOS: Avaliar a eficácia de um novo potencial antagonista transitório do receptor do canal vanilóide 1 (TRPV1) para pododermatite em cães.
UNASSIGNED: 24 cães de clientes com pododermatite. MATERIAIS E MÉTODOS: O estudo foi um ensaio clínico aberto, prospectivo, multicêntrico com cães de clientes. Todos os cães foram tratados duas vezes ao dia com um spray contendo pelargonato de hidroximetoxiiodobenzilglicolamida por 28 dias. As avaliações clínicas incluíram a escala analógica visual de prurido (PVAS), avaliação da qualidade de vida (QoL), presença de infecções secundárias e uma avaliação subjetiva de eficácia em quatro pontos pelo veterinário e pelo proprietário do cão.
RESULTS: Houve mais de 50% de melhora em todos os escores na conclusão do estudo. Infecções secundárias foram significativamente reduzidas. Ambos os veterinários e os proprietários de cães avaliaram a eficácia do produto positivamente. O produto foi bem tolerado. CONCLUSÕES E RELEVÂNCIA CLÍNICA: Este estudo demonstrou a tolerabilidade e a eficácia de um antagonista TRPV1 na pododermatite pruriginosa em cães.
INTRODUCCIÓN: El prurito es uno de los motivos más frecuentes de consulta dermatológica en la clínica veterinaria. El tratamiento suele ser multimodal y requiere monitorización y reevaluación continuas. Se necesitan nuevas terapias para ampliar el arsenal terapéutico. HIPÓTESIS/OBJETIVOS: Evaluar la eficacia de un nuevo antagonista del canal receptor transitorio de potencial vanilloide 1 (TRPV1) para la pododermatitis en perros. ANIMALES: 24 perros de propietarios particulares con pododermatitis. MATERIALES Y MÉTODOS: El estudio fue un ensayo clínico abierto, prospectivo y multicéntrico con perros de propietarios particulares. Todos los perros fueron tratados dos veces al día con un spray que contenía pelargonato de hidroximetoxiyodobencilglicolamida durante 28 días. Las evaluaciones clínicas incluyeron la escala analogs visual de prurito (PVAS), la valoración de las lesiones de la piel de la pata, la evaluación de la calidad de vida (QoL), la presencia de infecciones secundarias y una evaluación subjetiva de cuatro puntos de eficacia por parte del veterinario y el dueño del perro. RESULTADOS: hubo una mejora de más del 50 % en todas las puntuaciones al finalizar el estudio. Las infecciones secundarias se redujeron significativamente. Tanto los veterinarios como los dueños de perros evaluaron positivamente la eficacia del producto. El producto fue bien tolerado. CONCLUSIONES Y RELEVANCIA CLÍNICA: este estudio demuestra la tolerabilidad y eficacia de un antagonista de TRPV1 en la pododermatitis pruriginosa en perros.

Amongst the superfamily of transient receptor potential (TRP) channels, TRPV5 and TRPV6 are specialized members that mediate Ca2+-selective transport across epithelial membranes. Intriguingly, fluorescent fusion proteins of TRPV5 or TRPV6 are hardly discernible within the plasma membrane of living cells. Instead, TRPV6 is mostly found in vesicular membrane compartments, indicating either a rapid degradation or cycling of channel-bearing vesicles between endomembrane compartments and the plasma membrane. In TRPV6-expressing cells, brefeldin A, a toxin that blocks the transit between the endoplasmic reticulum and the Golgi apparatus, caused a drop in [Ca2+]i with a half time in the range of 0.5-1 h. Upon wash-out of the toxin, the [Ca2+]i rose to a steady-state level within 2-3 h. Consistently, the synchronized forward trafficking of TRPV6VL-eGFP after brefeldin A wash-out led to a visible accumulation of the protein within the plasma membrane, as shown by confocal and total internal reflection microscopy. Analysis of the internalization route and differentiation of vesicle populations provided evidence for a clathrin-dependent internalization pathway. Most TRPV6VL-bearing vesicles co-stained with Rab5a, a marker protein for early endosomes. Fewer vesicles were co-localized with Rab7a (late endosomes) or with Rab11 (recycling endosomes). From these data, we propose that the lack of plasma membrane visibility of the channel results from a rapid internalization, which in addition to transcriptional regulation, adds a layer of functional channel regulation to modulate transepithelial Ca2+ transport.

Anandamide (AEA) is one of the best characterized members of the endocannabinoid family and its involvement in many pathophysiological processes has been well documented in vertebrates and invertebrates. Here, we report the biochemical and functional characterization of key elements of the endocannabinoid system in hemocytes isolated from the Mediterranean mussel Mytilus galloprovincialis. We also show the effects of exogenous AEA, as well as of capsaicin, on the cell ability to migrate and to activate the respiratory burst, upon in vitro stimulation of phagocytosis. Interestingly, our findings show that both AEA and capsaicin suppress the hemocyte response and that the use of selective antagonists of CB2 and TRPV1 receptors revert their inhibitory effects. Overall, present data support previous evidence on the presence of endocannabinoid signaling in mollusks and advance our knowledge about the evolutionary origins of this endogenous system and its role in the innate response of mollusks.

Mechanical stretch raises intracellular Ca (Cai) in many cell types. Luminal flow-derived stretch stimulates O2- production by thick ascending limbs (THALs). Renal O2- is greater in Dahl salt-sensitive (SS) than salt-resistant (SR) rats. We hypothesized that mechanical stretch stimulates Ca influx via TRPV4 (transient receptor potential vanilloid type 4) which in turn raises Cai in THALs; these increases in Cai are necessary for stretch to augment O2- production; and stretch-stimulated, and therefore flow-induced, O2- production is enhanced in SS compared with SR THALs due to elevated Ca influx and increased Cai. Cai and O2- were measured in SS and SR THALs from rats on normal salt using Fura2-acetoxymethyl ester and dihydroethidium, respectively. Stretch raised Cai in SS by 270.4±48.9 nmol/L and by 123.6±27.0 nmol/L in SR THALs (P<0.02). Removing extracellular Ca eliminated the increases and differences in Cai between strains. Knocking down TRPV4 in SS THALs reduced stretch-induced Cai to SR levels (SS: 92.0±15.9 nmol/L; SR: 123.6±27.0 nmol/L). RN1734, a TRPV4 inhibitor, blunted stretch-elevated Cai by ≈75% and ≈66% in SS (P<0.03) and SR (P<0.04), respectively. Stretch augmented O2- production by 58.6±10.2 arbitrary fluorescent units/min in SS and by 24.4±2.6 arbitrary fluorescent units/min in SR THALs (P<0.05). Removal of extracellular Ca blunted stretch-induced increases in O2- and eliminated differences between strains. RN1734 reduced stretch-induced O2- by ≈70% in SS (P<0.005) and ≈60% in SR (P<0.01). Conclusions are as follows: (1) stretch activates TRPV4, which raises Cai in THALs; (2) the increase in Cai stimulates O2- production; and (3) stretch-induced O2- production is enhanced in SS THALs due to greater increases in Cai.

Previously, we showed that the synthetic nitroderivative trans-4-methyl-β-nitrostyrene (T4MeN) induced vasorelaxant effects in rat isolated aortic rings. Here, we investigated the mechanisms underlying the cardiovascular effects of T4MeN in normotensive rats. In pentobarbital-anesthetized rats, intravenous (i.v.) injection of T4MeN (0.03-0.5 mg/kg) induced a rapid (onset time of 1-2 s) and dose-dependent bradycardia and hypotension. These cardiovascular responses to T4MeN were abolished by bilateral cervical vagotomy or selective blockade of neural conduction of vagal C-fiber afferents by perineural treatment of both cervical vagus nerves with capsaicin. Hypotension and bradycardia were also recorded when T4MeN was directly injected in the right, but not into the left ventricle. Furthermore, they were significantly reduced by i.v. pretreatment with capsazepine but remained unaltered by ondansetron or suramin. In conscious rats, the dose-dependent hypotension and bradycardia evoked by T4MeN were abolished by i.v. methylatropine pretreatment. In conclusion, bradycardiac and depressor responses induced by T4MeN has a vago-vagal reflex origin resulting from the vagal pulmonary afferents stimulation. The transduction mechanism seems to involve the activation of vanilloid TRPV1, but not purinergic (P2X) or 5-HT3 receptors located on vagal pulmonary sensory nerves.

Anandamide, the first identified endogenous cannabinoid and TRPV1 agonist, is one of a series of endogenous N-acylethanolamines, NAEs. We have generated novel assays to quantify the levels of multiple NAEs in biological tissues and their rates of hydrolysis through fatty acid amide hydrolase. This range of NAEs was also tested in rapid response assays of CB1, CB2 cannabinoid and TRPV1 receptors. The data indicate that PEA, SEA and OEA are not endocannabinoids or endovanilloids, and that the higher endogenous levels of these metabolites compared to polyunsaturated analogues are a correlate of their slow rates of hydrolysis. The n-6 NAEs (AEA, docosatetraenoyl and docosapentaenoyl derivatives) activated both CB1 and CB2 receptors, as well as TRPV1 channels, suggesting them to be \'genuine\' endocannabinoids and \'endovanilloids\'. The n-3 NAEs (eicosapentaenoyl, docosapentaenoyl and docosahexaenoyl derivatives) activated CB2 receptors and some n-3 NAEs (docosapentaenoyl and docosahexaenoyl derivatives) also activated TRPV1 channels, but failed to activate the CB1 receptor. We hypothesise that the preferential activation of CB2 receptors by n-3 PUFA NAEs contributes, at least in some part, to their broad anti-inflammatory profile.

UNASSIGNED: Breast cancer is a malignant disease that represents an important public health burden. The description of new molecular markers can be important to diagnosis, classification, and treatment. Transient receptor potential vanilloid 1 (TRPV1) polymodal channel is expressed in different neoplastic tissues and cell lines of breast cancer and associated with the regulation of tumor growth, tumor neurogenesis, cancer pain, and malignant progression of cancer. In primary and metastatic breast cancer tumors, TRPV1 is expressed during neoplastic transformation, invasive behavior, and resistance to cytotoxic therapy.
UNASSIGNED: The objective of this study was to describe the subcellular distribution of TRPV1 in invasive breast carcinomas and its association with survival.
UNASSIGNED: In 33 cases of invasive breast carcinomas, we identified immunohistochemical and immunofluorescent expression patterns of TRPV1 compared to healthy breast tissue. We characterized the expression of TRPV1 induced by estrogens in breast cancer cell lines MCF-7 and MDA to establish a model of the TRPV1-estrogen relationship regarding the malignant potential. We examined the association of TRPV1 patterns with patients\' survival with the Kaplan-Meyer model, using the log-rank test at 5 years of follow-up. The relation of TRPV1 expression patterns to the St. Gallen breast cancer subtypes was also tested.
UNASSIGNED: Based on immunohistochemical expression pattern of TRPV1, we distinguished two main categories of breast cancer tissue, a \"classical category\" that exhibited diffuse expression of the channel and a \"non-classical category\" that expressed the channel in aggregates at the ER/Golgi and/or surrounding these structures. The classical pattern of TRPV1 was associated with a higher survival rate. In breast cancer cell lines, increasing doses of estrogens induced increased TRPV1 expression with nonclassical patterns at higher doses via a mechanism dependent on ER α.
UNASSIGNED: The expression and distribution of TRPV1 in invasive breast carcinomas may be considered as a biomarker for prognosis of the disease and a probable therapeutic target.

Activation of the hypothalamic-pituitary-adrenal axis (HPA) is critical for survival when the organism is exposed to a stressful stimulus. The endocannabinoid system (ECS) is currently considered an important neuromodulator involved in numerous pathophysiological processes and whose primary function is to maintain homeostasis. In the tissues constituting the HPA axis, all the components of the ECS are present and the activation of this system acts in parallel with changes in the activity of numerous neurotransmitters, including nitric oxide (NO). NO is widely distributed in the brain and adrenal glands and recent studies have shown that free radicals, and in particular NO, may play a crucial role in the regulation of stress response. Our objective was to determine the participation of the endocannabinoid and NOergic systems as probable mediators of the neuroendocrine HPA axis response to a psychophysical acute stress model in the adult male rat. Animals were pre-treated with cannabinoid receptors agonists and antagonists at central and systemic level prior to acute restraint exposure. We also performed in vitro studies incubating adrenal glands in the presence of ACTH and pharmacological compounds that modifies ECS components. Our results showed that the increase in corticosterone observed after acute restraint stress is blocked by anandamide administered at both central and peripheral level. At hypothalamic level both cannabinoid receptors (CB1 and CB2) are involved, while in the adrenal gland, anandamide has a very potent effect in suppressing ACTH-induced corticosterone release that is mainly mediated by vanilloid TRPV1 receptors. We also observed that stress significantly increased hypothalamic mRNA levels of CB1 as well as adrenal mRNA levels of TRPV1 receptor. In addition, anandamide reduced the activity of the nitric oxide synthase enzyme during stress, indicating that the anti-stress action of endocannabinoids may involve a reduction in NO production at hypothalamic and adrenal levels. In conclusion, an endogenous cannabinoid tone maintains the HPA axis in a stable basal state, which is lost with a noxious stimulus. In this case, the ECS dampens the response to stress allowing the recovery of homeostasis. Moreover, our work further contributes to in vitro evidence for a participation of the endocannabinoid system by inhibiting corticosterone release directly at the adrenal gland level.

BACKGROUND: Melastoma malabathricum L. (family Melastomaceae) has been traditionally used as remedies against various ailments including those related to pain. The methanol extract of M. malabathricum leaves has been proven to show antinociceptive activity. Thus, the present study aimed to determine the most effective fraction among the petroleum ether- (PEMM), ethyl acetate- (EAMM) and aqueous- (AQMM) fractions obtained through successive fractionation of crude, dried methanol extract of M. malabathricum (MEMM) and to elucidate the possible mechanisms of antinociception involved.
METHODS: The effectiveness of fractions (100, 250 and 500 mg/kg; orally) were determine using the acetic acid-induced abdominal constriction test and the most effective extract was further subjected to the hot plate- or formalin-induced paw licking-test to establish its antinociceptive profile. Further elucidation of the role of opioid and vanilloid receptors, glutamatergic system, and nitric oxide/cyclic guanosine phosphate (NO/cGMP) pathway was also performed using the appropriate nociceptive models while the phytoconstituents analyses were performed using the phytochemical screening test and, HPLC-ESI and GCMS analyses.
RESULTS: PEMM, EAMM and AQMM significantly (p < 0.05) attenuated acetic acid-induced nociception with the recorded EC50 of 119.5, 125.9 and 352.6 mg/kg. Based on the EC50 value, PEMM was further studied and also exerted significant (p < 0.05) antinociception against the hot plate- and formalin-induced paw licking-test. With regards to the mechanisms of antinociception,: i) PEMM significantly (p < 0.05) attenuated the nociceptive action in capsaicin- and glutamate-induced paw licking test.; ii) naloxone (5 mg/kg), a non-selective opioid antagonist, failed to significantly (p < 0.05) inhibit PEMM\'s antinociception iii) L-arginine (a nitric oxide precursor), but not NG-nitro-L-arginine methyl esters (L-NAME; an inhibitor of NO synthase), methylene blue (MB; an inhibitor of cGMP), or their respective combination, significantly (p < 0.05) reversed the antinociception of PEMM. Phytochemical analyses revealed the presence of several antinociceptive-bearing bioactive compounds, such as triterpenes and volatile compounds like oleoamide and palmitic acid. The presence of low flavonoids, such as gallocatechin and epigallocatechin, saponins and tannins in PEMM might synergistically contribute to enhance the major compounds antinociceptive effect.
CONCLUSIONS: PEMM exerted a non-opioid-mediated antinociceptive activity at the central and peripheral levels via the inhibition of vanilloid receptors and glutamatergic system, and the activation of NO-mediated/cGMP-independent pathway. Triterpenes, as well as volatile oleoamide and palmitic acid, might be responsible for the observed antinociceptive activity of PEMM.